I2‑Catalyzed Regioselective Oxo- and Hydroxy-acyloxylation ofAlkenes and Enol Ethers: A Facile Access to α‑Acyloxyketones, Esters,and Diol DerivativesRambabu N. Reddi, Pragati K. Prasad, and Arumugam Sudalai*

Chemical Engineering and Process Development Division, National Chemical Laboratory, Pashan Road, Pune, 411008, India

*S Supporting Information

ABSTRACT: I2-catalyzed oxo-acyloxylation of alkenes andenol ethers with carboxylic acids providing for the high yieldsynthesis of α-acyloxyketones and esters is described. Thisunprecedented regioselective oxidative process employs TBHPand Et3N in stoichiometric amounts under metal-freeconditions in DMSO as solvent. Additionally, I2-catalysisallows the direct hydroxy-acyloxylation of alkenes with thesequential addition of BH3·SMe2 leading to monoprotecteddiol derivatives in excellent yields.

α-Acyloxyketones and esters are significant building blockspresent in a variety of biologically interesting natural products,pharmaceuticals, and synthetic intermediates of broad utility.1 Inparticular, mandelic acid derivatives have shown antioxidant,2a

urinary antiseptic,2b anti-HIV,2c antitumor,2d antifungal,2e andantithrombic effects.2f Generally, these α-functionalized carbonylderivatives are prepared either by the substitution of α-halocarbonyl compounds3a/insertion of α-diazoketones3b withalkaline carboxylates or the direct oxidative coupling of ketoneswith toxic heavy metal oxidants [e.g., Pb(OAc)4, Tl(OAc)3,Mn(OAc)3, etc.]

4 and Ru-catalyzed addition of carboxylic acidsonto propargyl alcohols.5 Further, α-acyloxylation of carbonylcompounds is reported using N-methyl-O-benzoylhydroxyl-amine6 and benzoyl peroxide7 as a carboxylic acid source.However, in the above reports, prefunctionalization of ketones/carboxylic acids is required prior to the α-acyloxylation step.Recently, direct oxidative coupling of ketones with carboxylicacids using a hypervalent iodine catalyst in the presence of anexcess amount of BF3·OEt2 in wet AcOH, mCPBA

8 or peraceticacid9 as a co-oxidant has been reported to give α-acyloxyketones.Both intra- and intermolecular TBAI catalyzed oxidativecoupling of carbonyl compounds with carboxylic acids/benzylicalcohols using either H2O2 or TBHP as a co-oxidant have beenreported.10,11 However, these protocols suffer from certaindisadvantages such as use of a large excess of ketone motifs andco-oxidants, poor regioselectivity, and low yields. Moreover, theaforementioned methods are not suitable for α-acyloxylation ofesters. Generally, α-acyloxy esters are prepared by the oxidationof alkyl trimethylsilylketene acetals with Pb(IV) carboxylates.12a

In particular, mandelic acid derivatives are prepared by a metal-catalyzed intramolecular Cannizzaro reaction of α-ketoaldehy-des12b or Friedel−Crafts reaction of aromatic compounds withglyoxylates.12c

The dihydroxylation of alkenes has been elegantly demon-strated with various transition metal catalysts13 which are costly

and toxic that led to the emergence of metal-free dihydroxylationof alkenes.14 Again, the selective protection of one of the hydroxygroups in 1,2 diol is challenging and has been achieved usingexpensive reagents.15 Recently, an nBu4NI-catalyzed direct anduseful method for the synthesis of monoprotected diol fromalkenes with TBHP as co-oxidant has been reported, although itis limited to styrenic substrates only.16

In recent times, I2 catalysis, in combination with either aq.H2O2 or tert-butyl hydroperoxide as water-soluble co-oxidants,has been increasingly explored due to the environmentallybenign and inexpensive oxidation reagents in place of rare ortoxic heavy metal oxidants.17

To the best of our knowledge, use of catalytic electrophiliciodine in combination with stoichiometric co-oxidants fromalkenes is not known. In 1998, Komatsu et al. reported iodinecatalyzed aziridination of olefins using chloramine-T as the co-oxidant.18 Herein, we report for the first time, a catalyticmodification of the Woodward−Prevost oxidation for C−Obond formation using I2/TBHP catalyzed oxo-acyloxylation ofalkenes19 and enol ethers with carboxylic acids in DMSO assolvent and Et3N as base, giving α-acyloxyketones and esters(2a−z) in high yields and excellent regioselectivity (99%). Inaddition, one-pot “hydroxy-acyloxylation” has been described bysequential addition of BH3·SMe2 in the reaction mixture thatproduces monoprotected diol derivatives (3a−n) in excellentyields (Scheme 1).Initially, when styrene (1 mmol) was treated with a mixture

containing benzoic acid (1mmol), NBS (1mmol), and Et3N (1.2mmol) at 25 °C in DMSO, the corresponding α-benzylox-yketone 2a was obtained in 89% isolated yield with excellentregioselectivity (>99%) (Table 1). When a stoichiometric amountof I2 was used as a halogen source, 2a (90% yield) was indeed

Received: September 17, 2014

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obtained with perfect regioselectivity. Encouraged by the result,it was of interest to develop a catalytic version of this useful oxo-acyloxylation process.Thus, a series of experiments were conducted employing I2 in

catalytic amounts (10 mol %) along with other stoichiometricoxidants such as aq. H2O2, NaIO4, Oxone, or TBHP, which gave2a in 13%, 15%, 8%, and 88% yields, respectively. With 5 mol %of I2, a lowered yield of 2a (53%) was however observed. Furthermodification in the iodine source, base, or solvent system(DMSO in combination with other solvents) did not show anysignificant improvement in the product yield. Other carboxylicacids (acetic, p-nitrobenzoic, p-chlorobenzoic, nicotinic, andcrotonic acids) could be employed giving the corresponding oxo-acyloxylation products 4a, 4b, 4c, 4d, and 4e in 64%, 72%, 76%,74%, and 79% yields, respectively (Table 1).

The scope of the study was extended to substituted aromaticsand alkenes, the results of which are subsequently displayed inTable 2. Several olefins with varied functional groups were found

compatible in the reaction. Electron-neutral (4-CH3), electron-deficient (4-CN), and electron-rich [3,4-(OMe)2] groups on thearomatic nucleus were compatible and provided the correspond-ing products in excellent yields (82−85%, 2b, 2d, and 2f).Similarly, aliphatic olefins were found compatible under the

optimal conditions and provided (2g-n) in good yields (82−92%). Moreover, disubstituted alkenes (1m−1q) underwent thisoxo-acyloxylation smoothly providing the corresponding α-acyloxy ketones (2m−2q) in high yields with excellentregioselectivity (>99%, i.e. ketone group at the benzylicposition).We envisioned that addition of BH3·SMe2 to the reaction

mixture would enable us to obtain the corresponding diolderivatives 3a−q (Table 2). To our delight, we indeed found thatseveral styrenes and aliphatic alkenes underwent this “oxo-acyloxylation-reduction” process smoothly affording diol de-rivatives 3a−q in 72−90% yields and excellent chemoselectivity(99%). Notably, use of excess of BH3·SMe2 (2 equiv) to thereaction mixture afforded the corresponding diol in 82% yield(entry 7). Remarkably, internal alkenes gave the desired productsin good diastereomeric ratio (3:1) with high yields (entry 13 and14).Further, intramolecular version of hydroxy-acyloxylation wasdemonstrated in the macrolactonization of undec-10-enoic acid(1r), which gave 12 membered hydroxy lactone 3r in 82% yield(Scheme 2).19

Table 3 summarizes the application of the optimized reactionconditions to a range of enol ethers in an effort to expand thescope of this oxo-acyloxylation reaction. Enol ethers with p-substituted electron-rich or -poor groups and furan substitutionsproved to be good substrates for this transformation, affording

Scheme 1. I2-Catalyzed Oxo- and Hydroxy-acyloxylation ofAlkenes and Enol Ethers

Table 1. I2-Catalyzed Oxo-acyloxylation of Styrene withCarboxylic Acids: Optimization Studiesa

no.halogen

(10 mol %)oxidant(1 equiv) base R yield of 2b

1 NBSc − Et3N Ph (2a) 892 I2

c − Et3N Ph 903 I2 50% H2O2 Et3N Ph 134 I2 NaIO4 Et3N Ph 155 I2 Oxone Et3N Ph 86 NaI TBHP Et3N Ph trace7 nBu4NI TBHP Et3N Ph 11

8 I2 TBHP Et3N Ph 88 (53)d

(89)e

9 I2 TBHP NaH Ph 3910 I2 TBHP KOtBu Ph 7211 I2 TBHP DBU Ph 6712 I2 TBHP K2CO3 Ph 4713 I2 TBHP Et3N CH3 (4a) 6414 I2 TBHP Et3N 4-NO2-Ph

(4b)72

15 I2 TBHP Et3N 4-Cl-Ph (4c) 7616 I2 TBHP Et3N 3-pyridyl

(4d)74

17 I2 TBHP Et3N 1-propenyl(4e)

79

aReaction conditions: styrene (1 mmol), carboxylic acid (1 mmol),halogen source (10 mol %), base (1.2 mmol), TBHP (5−6 M indecane) (1 mmol); in 8 mL of DMSO, 25 °C, 12 h. bIsolated yieldafter column chromatographic purification. c1 equiv of halogen sourcewas used. d5 mol % of I2 was used.

e20 mol % of I2 was used.

Table 2. I2-catalyzed Oxo- and Hydroxy-benzoyloxylation ofAlkenes with Benzoic Acid: Substrate Scopea

product yields (%)b

no. alkenes (1a−n) 2a−n 3a−qc

1 styrene (1a) 88 862 4-CH3-styrene (1b) 85 843 4-Br-styrene (1c) 88 864 4-CN-styrene (1d) 82 795 4-OAc-styrene (1e) 84 836 3,4-(OMe)2 styrene (1f) 83 817 PMBO-CH-CHCH2 (1g) 83 82d

8 allyl acetate (1h) 91 899 1-hexene (1i) 88 8810 1-octene (1j) 92 9011 1-decene (1k) 89 8712 1-tridecene (1l) 86 8413 cyclohexene (1m) 82 83 (3:1)e

14 indene (1n) 76 72 (3:1)e

15 stilbene (1o) 78f −16 Ph-CHCH-CH3 (1p) 81f −17 Ph-CHCH-CH2-OTBS (1q) 84f −

aSee footnote a under Table 1. bIsolated yields after columnchromatographic purification. cIn situ addition of anhydrous Na2SO4and BH3·SMe2 (0.5 equiv) to conditions in footnote a in Table 1.dDiol was obtained after excess of BH3·SMe2 (2 equiv) was added.eAnti/syn ratio. f4-Nitrobenzoic acid was used instead of benzoic acid.

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the corresponding mandelic and lactic acid derivatives 2s−v inhigh isolated yields (74−82%).Aliphatic enol ethers (1w−y) also gave the desired products

2w−y in high yields. In addition, when cyclic enol ether 1z wasused, the desired product 2z was obtained in 84% yield.To gain some insight into the mechanism of the reaction, the

following experiments were performed: (i) no reaction wasobserved in the absence of either benzoic acid or Et3N; (ii) in thecase of styrene, the iodo compound II was isolated (20% yieldafter 2 h) and characterized completely (GC-MS, 1H and 13CNMR) which eliminates the role of hypervalent iodine in themechanism ; (iii) further treatment of II with DMSO and Et3Nafforded the desired product 2a in 62% yield; (iv) Table 1(entries 2 and 8) suggests that TBHP can be used as a co-oxidant.According to the aforementioned information and based on

previous reports, a proposed mechanism for this I2-catalyzedoxidative functionalization of alkenes is outlined in Scheme 3.Initially, the substrate alkene reacts with I2 to afford the iodoniumion intermediate I, which undergoes regioselective ring opening

with benzoic acid giving the iodo compound II. The proposedkey intermediate species III,14c formed from II by the anchimericassistance shown by the benzoate group, reacts with DMSO in aregioselective manner to give hydroxy ylide IVwith the liberationof an iodide ion. The iodide ion is then reoxidized with TBHP toregenerate I2 while elimination (−Me2S) from IV could then beundertaken to provide the desired products 2a−z, which onborane reduction gave diol derivatives 3a−n.Its application is illustrated in the total synthesis of

(+)-Tanikolide 7,20 a brine-shrimp toxin and antifungal marinemetabolite. Thus, α-benzoyloxyketone 2l, obtained from 1-tridecene by the present protocol, was subjected to asymmetricKeck allylation to give homoallylic alcohol 5 (81% yield; 81% ee).Compound 5was then subjected to cross-metathesis withmethylacrylate using Grubbs’ second generation catalyst to giveunsaturated ester 6 in 88% yields, which was finally reducedand hydrolyzed to afford (+)-Tanikolide in 85% yield (Scheme4).

In summary, we have demonstrated that the oxo- and hydroxy-acyloxylation process of alkenes and enol ethers with carboxylicacids can be achieved using metal-free catalytic systems. Thisoperationally simple and efficient method provides a newapproach toward the synthesis of α-acyloxyketones, esters (2a−z), and diol derivatives (3a−n) with a broad substrate scope. Webelieve that the macrolactonization directly from unactivatedcarboxylic acid would serve as a competent method and findtremendous applications in the synthesis of widely occurringmacrolides. More importantly, this inexpensive catalyst/oxidantsystem provides for a single-step, metal-free dihydroxylationprocess directly from alkenes, thereby complimenting OsO4

catalyzed dihydroxylation of alkenes.

Scheme 2. I2-Catalyzed Hydroxy-lactonization of Undec-10-enoic Acid

Table 3. I2-Catalyzed Oxo-benzoyloxylation of Enol Etherswith Benzoic Acid: Substrate Scopea

aFor reaction conditions, see footnote a under Table 1: Bz = benzoyl.

Scheme 3. Probable Catalytic Cycle for Oxo- and Hydroxy-acyloxylation of Alkenes

Scheme 4. Synthesis of (+)-Tanikolide

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■ ASSOCIATED CONTENT*S Supporting Information

Experimental procedures, product characterization, copies ofNMR spectra for 2a−z, 3a−n, 4−7. This material is available freeof charge via the Internet at http://pubs.acs.org.

■ AUTHOR INFORMATIONCorresponding Author

*E-mail: a.sudalai@ncl.res.in.Notes

The authors declare no competing financial interest.

■ ACKNOWLEDGMENTSR.B.R. and P.K.P. thank CSIR, New Delhi for the award ofresearch fellowships and DST (No. SR/S1/OC-67/2010) NewDelhi for financial support. The authors also thank Dr. V. V.Ranade, Chair, Chem. Eng. & Process Develop. for hisencouragement.

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